Preparation of 2-bornane alkyl ketones



United States Patent ce Patented fffifflfi:

ketone product (I) include, for example, chromic acid, 3,481,985 potassium permanganate, etc.; however, it is to be under- PREP gg gg stood that any functionally equivalent reagent which is Robert L. Bugianesi, Comma, and Bruce Lin, Plaim capable of converting an organoborane compound to its field, N.J., assignors to Merck & Co., Inc., Rahway, 5 Corresponding ketone may also be employed 1n an analo- N.J., a corporation of New Jersey gus manner to yield an identical product. Also, the step of No Drawing. Filed May 1, 1967, Ser. No. 634,879 treating camphor with a suitable 2-alkylidene triphenyl- C076 /00 phosphorane reagent is most advantageously conducted 260-587 10 Claims with the application of slight heating as, for example, by

10 heating at temperatures in the range of 60-80" C.; how ever, it should be noted that the application of heat is simply catalytic in its effect and is not critical to the suc- ABSTRACT OF THE DISCLOSURE A new method for the preparation of 2-bornane alkyl cess of the reaction. The following equation illustrates the ketones (I) which comprises: (a) treating camphor with process:

/ 'CHr-C-CH; CH3-CCH3 =0 +RCH=P T 3 CH3 CH3 (II) (III) z al CHg-C-CH: -oHR- BH Oxidation} om-o-on ff l OR an alkylidene triphenylphosphorane to yield an alkylidenewherein R is alkyl and preferably lower alkyl such as bornane; (b) followed by the reaction of the alkylidenemethyl, ethyl, propyl, butyl, etc. The diborane reagent embornane intermediate thus obtained with diborane to form ployed in the conversion of Z-alkylidenebornane (III) to a bis-[alpha-alkyl-(2 bornane)methyl]borane; and (0) its bis-organoboranecounterpart (IV) may either be added treating the bisorganoborane thus obtained with a suitable per se to the reaction mixture as illustrated in the preoxidizing agent to yield the desired ketone product (I). ceding equation or, alternatively, it may be generated in situ as, for example, by the dropwise addition of lithium aluminum hydride in ether to a solution of the 2-alkyli- This invention relates to a novel method for the prepadenebornane (III) in boron trifluoride etherate. ration of 2-bornane alkyl ketones. The 2-bornane alkyl ketone products (I) of the instant The ketone products of this invention are known comprocess are generally obtained as oily which may be pounds which have been synthesized by several alternate taken up in suitable solvents such as pentane and which routes; however, the known methods of preparation inmay then be washed, dried and purified in the convenvariably result in an impure product which contains a relational manner as, for example, by distillation or by chrotively large proportion of unreacted starting material and matography via treatment with an appropirate eluant such as a mixture of pentane and ethyl ether.

The alkylidene triphenylphosphorane reagents emundesirable side products.

It has now been found that 2-bornane alkyl ketones may be obtained in good yield and in a higher state of ployed as starting materials in the foregoing reaction with purity than has heretofore been possible by prior art syncamphor are conveniently obtained by the reaction of a theses. The instant process consists in treating camphor strong base such as sodium hydride or potassium tert.-

(II, infra) with an alkylidene triphenylphosphorane to obbutoxide with dry dimethylsulfoxide under nitrogen and tain a 2-alkylidenebornane (III, infra) and the bornane with slight heating to yield the corresponding methylsulintermediate thus obtained is then treated with diborane finyl carbanion and the carbanion intermediate thus obto yield a his [alpha-alkyl (2 bornane)methyl]borane tained is then treated with a suitable alkyl triphenylphos- (IV, infra) which is oxidized by treatment with a suitable phonium halide to yield the desired alkylidene-phosphoroxidizing agent to yield the desired 2-bornane alkyl keane' derivative. When the strong base employed is sodium tone (I, infra). Oxidizing agents which are suitable for hydride the reaction mixture containing the sodio methylconverting the bis-organoborane intermediate (IV) to the sulfinyl carbanion intermediate is a highly explosive mixture and, therefore, extreme caution must be exercised in its handling. However, we have found that when potassium tert.-butoxide is substituted for sodium hydride in an otherwise analogous reaction the carbanion mixture thus obtained is not a hazard and the danger of an explosion is effectively overcome. The following equation illustrates the preparation of the phosphorane intermediates:

wherein X is halogen, for example, chlorine, bromine, etc. and R is as defined above.

The examples which follow illustrate the method by which the Z-bornane alkyl ketones are prepared. However, the examples are illustrative only and it Will be apparent to those having ordinary skill in the art that all of the ketone products embraced by general Formula I, supra, may be obtained in an analogous manner by substituting the appropriate starting materials for those set forth in the examples.

EXAMPLE 1.L-2-BORNANE METHYL KETONE Step A Ethylenetriphenylphosphorane A mixture of sodium hydride (6.2 g., 0.27 mole) and dry dimethyl sulfoxide (500 ml.) is heated at 80-85 C. with stirring under nitrogen until the evolution of hydrogen ceases (approximately 45 minutes). The solution of sodio methylsulfinyl carbanion thus obtained is then cooled to C. and maintained at that temperature while ethyl triphenylphosphonium bromide (100 g., 0.27 mole) is added with stirring. After stirring an additional minutes the resulting red solution thus obtained is identified as ethylenetriphenylphosphorane.

Step A Ethylenetriphenylphosphorane Step B: L-Z-ethylenebornane d-Camphor (36.0 g., 0.24 mole) is added to the ethylenetriphenylphosphorane obtained according to either of the preceding steps. Pentane (30 ml.) is then added to return sublimed camphor from the water condenser and the resulting mixture is stirred at 70 C. for 20 hours under nitrogen. Upon cooling, water (90 ml.) and pentane (200 ml.) are added to the reaction mixture to separate the product. The aqueous dimethyl sulfoxide layer then is extracted with three additional portions of pentane and the combined pentane solutions are washed thoroughly with water, then with dilute hydrochloric acid, washed again with water, then with sodium bicarbonate solution and again with water. After drying over magnesium sulfate, the solution is poured onto a column containing one pound of neutral alumina. The product is then eluted with pentane and the solvent removed by distillation through a fractionating column. There is thus obtained 27 g. (77% of L-2-ethylenebornane. The structure of the product is confirmed by infra-red and nuclear magnetic resonance analysis. The nuclear magnetic resonance spectrum for the product in carbon tetrachloride shows the ring methyl peaks at 8.85, 9.13 and 9.18 T and one olefinic proton as a multiplet at about 4.9 T downfield from tetramethylsilane.

4 Step C: L-2-bornane methyl ketone L-2-ethylenebornane (26 g., 0.160 mole) is treated with diborane which has been generated in situ by the dropwise addition at room temperature of a solution of lithium aluminum hydride (24 g., 0.590 mole) in ether (200 ml.) to 47% boron trifluoride etherate (24 g., 0.785 mole) in dry ethyl ether (300 ml.) with stirring. Stirring is continued at room temperature for two hours. Excess hydride is then decomposed by the dropwise addition of Wet ether followed by the addition of water (25 ml.). The organobornane thus obtained is oxidized by the dropwise addition of a chromic acid solution [prepared from sodium dichromate dihydrate (35.6 g., 0.118 mole) and 96% sulfuric acid (26.4 ml.) in water ml.)] with stirring while maintaining the reaction mixture at 25-30 C. The resulting mixture is then heated at reflux for two hours, cooled and the product extracted thrice with pentane. The combined pentane solutions are thoroughly washed with water, then with sodium bicarbonate solution, and again with water. The solution then is dried over magnesium sulfate and the solvent removed by distillation to yield 35 g. of an oily residue. The residue is dissolved in pentane and the resulting solution passed onto a column containing 350 g. of silica gel packed in pentane. The column is then washed with pentane and the product eluted with pentane-ethyl ether (9:1) to yield 16.5 g. (56%) of L-2-bornane methyl ketone. An analytical sample of the product is distilled to give pure L-2-bornane methyl ketone having a boiling point of 102 C. at 11 mm. mercury; 11 1.4795, [u] +1.6.

Analysis-Calculated for C H O: C, 79.94; H, 11.18. Found: C, 79.72; H, 11.09.

In a manner similar to that described in Example 1 for the preparation of L-2-bornane methyl ketone all of the 2-bornane alkyl ketones embraced by this invention may be obtained. Thus, for example, by substituting the appropriate alkyl triphenylphosphonium halide for the ethyl triphenylphosphonium bromide of Example 1, Step A or A and the desired oxidizing agent for the reagent described in Step C and following the procedure described in Steps A-C of that example all of the 2-bornane alkyl ketone products (I) may be obtained. The following equation illustrates the process described in Example 1, Steps A A B and C, together with Table I (infra) describes the alkyl triphenylphosphonium halide starting materials of the instant process and the products (I) CHs-C-CHzl III NaH (CHahSO A CHBSOCHT' 2 C2H5 3 --(CH2)3CH3 4 (CH2)2CH3 5 (CH2)4CH3 125 C. 169 C. 147 C. 191 C.

Potassium permanganate. Chromic acid. Potassium permanganate. Chromic acid.

The 2-bornane alkyl ketones (I) prepared by the instant process are useful as intermediates in the preparation of compounds having valuable pharmacological activity; therefore, the present process constitutes an especially advantageous contribution to the art since it not only produc s the said ketones in good yield but in a high state of purity. As an illustration of this intermediate use of the following example can be cited: a 2-bornane alkyl ketone prepared acocrding to the instant process is first epimerized by passage through a column of basic alumina and the endo 2-bornane alkyl ketone thus obtained is then converted to the corresponding oxime by treatment with hydroxylamine hydrochloride in a basic solution followed the addition of an acid and the resulting endo Z-bornane alkyl oxide thus obtained is then reduced to the corresponding alkyl (endo-2-bornane)- methylamine salt. The amine salt thus obtained is a valuable chemotherapeutic agent which is useful, in vivo, against viral respiratory diseases and particularly against the influenza and flu viruses.

It will be apparent from the foregoing description that the 2-bornane alkyl ketone products (I) of this invention constitute a valuble class of compounds which have not been prepared heretofore. One skilled in the art will also appreciate that the processes disclosed in the above examples are merely illustrative and are capable of a wide variation and modification without departing from the spirit of this invention.

What is claimed is:

1. A process for the preparation of a compound having the formula:

wherein R is alkyl; which comprises reacting dry dimethylsulfoxide with a strong base to form a methylsulfinyl carbanion followed by the reaction of the carbanion intermediate thus obtained with an alkyl triphenylphosphonium halide to yield the corresponding alkylidene triphenylphosphorane; the said alkylidene triphenylphosphorane is then reacted with camphor to form a 2-alky1- idenebornane and the bornane intermediate thus obtained is then treated with diborane to afford a bis-[alpha-alkyl- (2-bornane)methyl]borane Which is then oxidized with chromic acid or potassium permanganate to yield the desired product.

2. The process of claim 1 wherein the strong base employed in the reaction with dimethylsulfoxide is sodium hydride.

3. The process of claim 1 wherein the strong base employed in the reaction with dimethylsulfoxide is potassium tert.-butoxide.

4. The process of claim 1' wherein the alkyl triphenylphosphonium halide employed is ethyl triphenylphosphonium bromide.

5. A process according to claim 1 for the preparation of L-2-bornane methyl ketone which comprises reacting dry dimethylsulfoxide with a strong base to form a methylsulfinyl carbanion followed by the reaction of the carbanion intermediate thus obtained with ethyl triphenylphosphonium bromide to yield the corresponding ethylenetriphenylphosphorane; the said phosphorane is then reacted with d-camphor to form an L-Z-ethylenebornane and the bornane thus obtained is treated with diborane to afford a bis [alpha-methyl-(2-bornane)methyl] borane which is then oxidized with chromic acid to yield the desired product.

6. A process for the preparation of a compound having the formula:

wherein R is alkyl; which comprises treating camphor with an alkylidene triphenylphosphorane to form a 2- alkylidenebornane followed by the reaction of the bornane intermediate thus obtained with diborane to afford a bis- [alpha-alkyl-(2-bornane)-methyl]borane which is then oxidized with chromic acid or potassium permanganate to yield the desired product.

7. The process of claim 6 wherein the alkylidene triphenylphosphorane employed is ethylene triphenylphosphorane.

8. The process of claim 6 wherein the camphor reactant employed is d-camphor.

9. The process of claim 6 wherein the oxidizing agent employed is chromic acid.

10. A process according to claim 6 for the preparation of L-Z-borane methyl ketone which comprises treating d-camphor with ethylenetriphenylphosphorane to form L-2-ethylenebornane followed by the reaction of the bornane intermediate thus obtaned with diborane to afford a bis-[alpha-methyl-(2-bornane)methyl]borane which is then oxidized with chromic acid to yield the desired product.

References Cited Zwiefel, Org. Reactions, vol. 13, pp. 22 and 23 (1963).

Greenwald, J. Org. Chem. vol. 28, pp. 1128 to 1129 (1963).

Maercker, Org. Reactions vol. 14, p. 446 (1965).

Zwiefel, Org. Reactions, vol. 13, pp. 24 to 30, 39 and 53 (1963).

LEON ZITVER, Primary Examiner M. M. JACOBS, Assistant Examiner U.S. Cl. X.R. 260-6065, 666 

